Preparation of noroxymorphone from morphine

ABSTRACT

The invention provides processes for the conversion of normorphinone and its derivatives, which can be synthesized from morphine, to the corresponding 14-hydroxynormorphinone and its derivatives including oxycodone, oxymorphone, noroxymorphone and naltrexone. Noroxymorphone is a key intermediate for the production of important narcotic analgesics and antagonists. The invention also provides certain novel intermediates.

RELATED APPLICATIONS

This application is a divisional application of Ser. No. 08/893,464filed Jul. 11, 1997 now U.S. Pat. No. 5,869,169, which is herebyincorporated by reference and is based on provisional patent applicationSer. No. 60/022,685, filed Jul. 26, 1996, and provisional patentapplication Ser. No. 60/045,081, filed Apr. 29, 1997.

BACKGROUND OF THE INVENTION

1) Field of the Invention

This invention relates in general to process for the conversion ofnormorphinone and its derivatives, which can be synthesized frommorphine, to the corresponding 14-hydroxynormorphinone and itsderivatives including oxycodone, oxymorphone, noroxymorphone, andnaltrexone. Noroxymorphone is a key intermediate for the production ofimportant narcotic analgesics and antagonists. In another aspect, theinvention is directed to certain novel intermediates.

2) Background Art

14-Hydroxy-substituted morphine derivatives are important narcoticanalgesics and/or antagonists. These drugs include oxycodone,oxymorphone, nalbuphine, naloxone, naltrexone, and nalmefene. They arereadily synthesized from thebaine, which is a minor component of gumopium. As the supply of thebaine is limited and the demand isincreasing, therefore, the price of thebaine is high. As a result, manyalternative approaches have been made for the preparation of14-hydroxymorphine derivatives.

The reported efforts for preparing these narcotics bearing a 14-hydroxygroup from readily abundant starting materials morphine or codeine (aminor component of gum opium, which may also be synthesized bymethylation of morphine) are summarized as the following: (1) theconversion of codeine to thebaine through dihydrocodeinone (5.4% yield,H. Rapoport, et al., J. Am. Chem. Soc., vol. 89, 1967, p. 1942 and H.Rapoport, et al., J. Org. Chem., vol. 15, 1950, p. 1103), codeinone (20%yield, I. Seki, Chem. Pharm. Bull., vol. 18, 1970, p. 671 and H.Rapoport, et al., J. Am. Chem. Soc., vol. 77, 1955, p. 490) or 6-methylether of codeine (using manganese dioxide, 67% yield, R. B. Barber, etal., J. Med. Chem., vol. 18, 1975, p. 1074); (2) the oxidation ofcodeinone pyrrolidinyl di-enamine to 14-hydroxycodeinone (30-40% yield,I. Seki, Chem. Pharm. Bull., vol. 18, 1970, p. 671); (3) the directallylic oxidation of codeine to the corresponding 14-hydroxy derivativeswith manganese dioxide (I. Brown, et al., J. Chem. Soc., 1960, p. 4139),and selenium dioxide plus t-butyl hydrogen peroxide (M. A. Schwartz, etal., J. Med. Chem., vol. 24, 1981, p. 1525); and (4) the six-steptransformation of codeine to noroxycodone (52% yield) and noroxymorphone(43% yield) using photochemically generated singlet oxygen (M. A.Schwartz, et al., J. Med. Chem. vol. 24, 1981, p. 1525); and (5) thepreparation of noroxymorphone from morphine through an intermediate withcarbamate protection on the nitrogen atom (17-position) or a carbonateprotecton at the 3 position and the carbamate protection at the 17position of normorphinone dienol acetate with MCPBA in the substantialabsence of water (37% yield, Wallace, U.S. Pat. No. 5,112,975). Theseprocesses suffer from either low yields, long steps, not amenable toscale-up, or involve the use of environmentally unfriendly heavy metals.

It is therefore an object of the present invention to provide methodsfor the conversion of normorphinone and its derivatives to thecorresponding 14-hydroxynormorphinone and its derivatives. A furtherobject of the invention is to provide processes which provide relativelyhigh yields of the desired products. Another object is to providemethods which are environmentally safe and avoid the use of heavymetals.

Another object of the present invention is to provide processes whichcan use morphine or codeine as starting material instead of the scarcethebaine. Codeine is a component of gum opium and can also be producedby methylation of morphine using known prior art techniques. A stillfurther object of the present invention is to provide the use of anaqueous system in the oxidation step to form 14-hydroxynormorphinonewhich is not only environmentally friendly, but also desirable in whichto conduct the subsequent hydrogenation reaction without the need forisolating the 14-hydroxynormorphinone intermediate. A still furtherobject is to provide certain intermediates which are novel compositions.It is a further object of this invention to provide intermediates forspecific products, such as oxycodone, oxymorphone, naltrexone andnoroxymorphone. These and other objects will readily become apparent tothose skilled in the art in light of the teachings herein disclosed.

SUMMARY OF THE INVENTION

In its broad aspect, the present invention pertains to processes for thepreparation of 1 4-hydroxy-normorphinones of the formula: ##STR1## ancertain derivatives thereof as hereinafter indicated. In the formulaabove R is selected from the group consisting of lower alkyl of 1-7carbon atoms, cycloalkylalkyl with 3-6 ring carbon-atoms benzyl andsubstituted-benzyl having the formula: ##STR2## wherein Q and Q' areindividually selected from hydrogen, lower alkyl, trifluoromethyl,nitro, dialkylamino, cyano;

preferably, R is methyl (when the desired products are oxycodone andoxymorphone), cyclopropylmethyl (when the desired products arenaltrexone and nalmefene), cyclobutylmethyl (when the desired product isnalbuphine), and benzyl (when the desired products are naloxone,naltrexone, nalbuphine, or nalmefene);

R' is methyl, ethyl, 2-(4-morpholinyl)ethyl, benzyl, substituted-benzyl(as defined above), benzyloxycarbonyl or the group having the formula:

    R"C(O)--

wherein: R" is lower alkyl of 1-4 carbon atoms;

preferably, R' is methyl (when the desired product is oxycodone), benzyl(when the desired products are oxymorphone and14-hydroxyl-normorphinones), or acyl (when the desired product isoxymorphone) and R" is methyl;

from the corresponding normorphinones having the formula: ##STR3##wherein R and R' are as defined above; by reacting the normorphinones(as defined above) either (1) or (2) of the following processes:

(1) directly with an oxidizing agent, hydrogen peroxide, at atemperature of about 15° C. to about 70°, preferably 40° C. to 50° C.,in the presence of an acid such as formic acid, tartaric acid, aceticacid, or other mineral acids, preferably formic acid; in a suitablenon-reactive solvent such as water, acetic acid, THF, DMSO or a mixtureof solvents such as ETOAc/H₂ O suitable for solubilizing or suspendingthe reactants, preferably water, for a period of 1 to 24 hours, whichdepends on the scale of the reaction; or

(2) in a two-step manner by first with an acyl halide having theformula:

    R"C(O)X

wherein: R" is defined above, preferably methyl;

X is Cl or Br, preferably Cl;

or an acid anhydride having the formula:

    [R"C(O)].sub.2 O

wherein R" is as defined above;

and the corresponding acid salt having the formula:

    R"COOM

wherein: R" is as defined above,

M is sodium or potassium atom, preferably sodium atom; with or without acosolvent such as toluene, DMF, or DMAC, preferably toluene; heating ata temperature of about 60° C. to about 150° C., preferably 110° C. for 1to 24 hours, depending on the scale of the batch, to produce the dienolacylate having the formula: ##STR4## wherein: R, R', and R" are definedas above; then followed by reacting the dienol acylate with either anoxidizing agent under the conditions described in (1) or reacting with aperoxyacid such as 3-chloroperoxybenzoic acid (MCPBA) in a weak acidsuch as acetic acid or formic acid, with or without water and with orwithout a cosolvent, to help dissolve the peroxyacid and the reactant.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The embodiments of the present invention will be discussed withreference to various examples of reactions via which the3(O)-substituted- and/or 17(N)-substituted-14-hydroxynormorphinone canbe prepared. The R, R' and R" are as previously defined above.

Key features of the novel reactions of the invention are made possibleby the combination of several essential novel concepts and techniques,and reside in

(a) the conversion of the 17(N),3(O)-substituted normorphinone havingthe formula: ##STR5## to the corresponding14-hydroxy-17(N),3(O)-substituted-normorphinone having the formula:##STR6## with hydrogen peroxide in an aqueous system in the presence ofan acid; (b) the conversion of the 17(N),3(O)-substituted-normorphinonedienol acylate having the formula: ##STR7## to the corresponding14-hydroxy-17(N),3(O)-substituted-normorphinone having the formula:##STR8## with an oxidizing agent chosen from aqueous hydrogen peroxideor a peroxycarboxylic acid in an aqueous system in the presence of aweak organic acid;

(c) the oxidation reaction to form14-hydroxy-17(N),3(O)-substituted-normorphinone having the formula:##STR9## in an acetic aqueous system, which is very desirable for thefollowing catalytic hydrogenation step;

(d) the 14-hydroxy 3(O)-substituted and/or17(N)-substituted-normorphinone having the formula: ##STR10## mayfurther react in specific ways to form oxycodone, oxymorphone,naltrexone, and noroxymorphone. The later is a common intermediate fornaloxone, naltrexone, nalmefene, and nalbuphine;

(e) the choice of a preferred substitution group depends on the kind ofdesired product in such a way to facility the ease of operation, solventand reagent consumption.

The advantages of the method of the invention for the preparation ofoxycodone include, among others:

(a) the use of a currently abundant starting material, codeine, which isa minor component of gum opium and can also be produced by methylationof morphine using prior art techniques. This method does not need todemethylate the N-methyl group on the 17 position of codeine, protectthe 17-nitrogen of norcodeine and norcodeinone with a carbamate and thendeprotect the 14-hydroxy-N-ethoxycarbonyinorcodeinone, finally,remethylate the same nitrogen as disclosed in U.S. Pat. Nos. 4,472,253,4,639,520 and 4,795,813;

(b) the use of an aqueous system in the oxidation of normorphinones ornormorphinone dienol acyletes is not only environmentally friendly butalso desirable for the following hydrogenation reaction, since there isno need to isolate the intermediate 14-hydroxycodeinone. The basicnitrogen on the 17-position is protonated in the acidic aqueous system.This greatly contributes to the high solubility of the reactant and theproduct.

This novel synthesis route affords high yields, good reliability, andstraightforward operation and control at each and every step of thesynthesis and a major reduction in the cost of the synthesis ofoxycodone, oxymorphone, noroxymorphone, naltrexone and nalbuphine.

Thus, for the synthesis of oxycodone from codeine in this invention, thestarting material, which has the formula: ##STR11## is converted tocodeinone having the formula: ##STR12## by the prior art method such asSwern oxidation (DMSO/acid halide or acid anhydride).

In the first method of this invention, codeinone is reacted withhydrogen peroxide in water in the presence of an acid at about 15° toabout 70° C. for a period of time depending on the scale of the reactionto afford 14-hydroxycodeinone in good yield. 14-Hydroxycodeinone soproduced is hydrogenated in the same reaction media with a catalyst toafford oxycodone in good yield. Preferably the temperature is betweenabout 40° to about 50° C. and the acid is formic acid.

The sequence of steps in the first method for the synthesis of oxycodonefrom morphine or codeine can be illustrated as follows: ##STR13##

In this and the reaction sequences which are hereinafter shown, thehyphenated two digit descriptor appearing beneath each formulacorrsponds to the same discriptor appearing after the title to theExamples. Accordingly, the solvents, reactants, temperatures, times andyield are set forth in the examples for each step of the overallreaction.

In the present invention it was observed that the yields of theintermediate products were markedly increased by first acylating thenormorphinones to the corresponding dienol acylates and then oxidizingthe acrylates to the corresponding 14-hydroxynormorphinones as opposedto the direct oxidation of normorphinones to the corresponding14-hydroxynormorphinones. Although this involves an extra step, theoverall yield is higher. For example, the oxidation of codeinone dienolacetate to 14-hydroxycodeinone provided a yield of 70 to 80% afterchromatography whereas direct oxidation of codeinone to the14-hydroxycodeinone gives about 40% yield.

Accordingly, in a second method of this invention, codeinone is firstconverted to codeinone dienol acetate by prior art methods (DE 902257,1957 and I Brown, JCS, 1960, p. 4139) and then the codeinone dienolacetate is reacted with hydrogen peroxide under the conditions set forthin the first process to 14-hydroxycodeinone which is hydrogenated tooxycodone in excellent yields. Alternatively, codeinone dienol acetateis reacted with a peroxyacid oxidizing agent in an aqueous ornon-aqueous system with a weak acid at room temperature to form14-hydroxycodeinone in excellent yield. Again the product,14-hydroxycodeinone, in its reaction mixture is suitable for the nextreaction, the catalytic hydrogenation, without isolation of the14-hydroxycodeinone by adding the catalyst and hydrogenating the mixtureand then isolating oxycodone. Preferably the peroxyacid oxidizing agentis 3-chloroperbenzoic acid, perbenzoic acid, peroxyacetic acid; morepreferably 3-chloroperbenzoic acid. A non-reactive cosolvent such asethyl acetate, tetrahydrofuran, dioxane, is used to dissolve theoxidizing agent. The preferred weak acid is acetic acid or formic acid,which also serves as the solvent. Conducting the reaction with orwithout water or oxalic acid does not change the yield.

The sequence of steps for the second method wherein codeinone isconverted to codeinone dienol acetate in the synthesis of oxycodone frommorphine can be illustrated as follows: ##STR14##

For the synthesis of oxymorphine from morphine in the present invention,

(a) the first step is to protect the phenolic hydroxy on the 3-positionof morphine to form the 3(O)-protected-morphine having the formula:##STR15## wherein P=P₁ or P₂. P is a suitable protecting group which isstable under the reaction conditions and easily removable by mildhydrolysis with an acid or base (for P₁) or under catalytichydrogenation (for P₂). P₁ includes acyl, benzoyl and alkoxycarbonyl. P₂includes benzyl, substituted benzyl and benzyloxycarbonyl.

(b) the second step is to oxidize the 3(O)-protected morphine to3(O)-protected-morphine having the formula: ##STR16## by any of theprior art methods such as Swern oxidation (DMSO/acid halide or acidunhydrite).

(c) the third step is to convert the 3(O)-protected-morphinone to the14-hydroxy-3-(O)-protected-morphinone using the techniques disclosed inthis invention as set forth in the conversion of codeinone to14-hydroxy-codeinone in the synthesis of oxycodone.

The intermediate, 3(O)-protected-codeinone dienol acylate, is a novelcompound having the formula: ##STR17## wherein P and R" are as definedabove; preferably P₁ is acetyl and P₂ is benzyl.

(d) depending on the particular protection group, P₁ or P₂, the fourthstep is either (i) to first produce the 7,8-double bond of 3-(O)-P₁-protected morphinone and then to remove the protection group by acid orbase hydrolysis to produce oxymorphone or (ii) to hydrogenate the7,8-double bond and deprotect simultaneously the 3-(O)-P₂ -protectedmorphinone to oxymorphone.

This synthesis of oxymorphone from morphine wherein P₁ is acetyl can beillustrated below: ##STR18## wherein the hyphenated two digits beloweach formula identifies this corresponding examples as previouslyindicated.

The synthesis of oxymorphone from morphine wherein P₂ is benzyl can beshown as follows: ##STR19##

For the synthesis of noroxymorphone from morphine in another embodimentof this invention, morphine is converted to 3-benzylmorphine, which isacetylated to 6-acetyl-3-benzlmorphine having the formula: ##STR20##6-acetyl-3-benzylmorphine is N-de-methylated with 1-chloroethylchloroformate or cyanogen bromide and followed by acid hydrolysis to3-benzylnormorphine. 3-Benzyinormorphine is reacted with benzyl halidein the presence of a base such as sodium or potassium bicarbonate toproduce 3,17-dibenzylnormorphine, a novel compound, which is oxidized to3,17-dibenzylnormorphinone, a novel compound, by Swern oxidation. Usingthe conditions set forth in this invention, 3,17-dibenzylnormorphinoneis oxidized to 3,17-dibenzyl-14-hydroxynormorphinone either by directlyreacting with hydrogen peroxide in formic acid or by first converting to3,17-dibenzylnormorphinone dienol acylate, a novel compound, and thenreacting the latter with hydrogen peroxide in formic acid or aperoxyacid as set forth in the synthesis of oxycodone. Without isolationof 3,17-dibenzyl-14-hydroxynormorphinone from its reaction mixture it ishydrogenated to remove the two benzyl groups and reduce the 7,8-doublebond simultaneously to produce noroxymorphone in good yields.

The synthesis of noroxymorphone from morphine can be illustrated asfollows: ##STR21##

For the synthesis of 3-methylnaltrexone from codeine in this invention,codeine is converted to 6-acetylcodeine, which is N-demethylated to6-acetylnorcodeine hydrochloride, followed by alkylating the nitrogen toform 17-cyclopropylmethylnorcodeine. The latter is oxidized to17-cyclopropylmethylnorcodeinone. As set forth in the synthesis ofoxycodone in this invention, 17-cyclopropylmethylnorcodeinone isconverted to 14-hydroxy-17-cyclopropylmethylnorcodeinone either byoxidizing with hydrogen peroxide in formic acid; or by first convertingto 17-cyclopropylmethylnorcordeinone dienol acetate, a novel compound,then oxidizing with either hydrogen peroxide or MCPBA. 14-Hydroxy-17-cyclopropylmethylnorcodeinone is hydrogenated to3-methylnaltrexone. 3-Methylnaltrexone can be demethylated to naltrexonewith BBr₃, a prior art method. The reaction can be illustrated asfollows: ##STR22##

For the synthesis of naltrexone from morphine in this invention,morphine is converted to 3-benzylnormorphine as described above in thesynthesis of noroxymorphone. 3-Benzylnormorphine is reacted withcyclopropylmethyl halide to produce3-benzyl-17-cyclopropylmethylnormorphine, a novel compound, which isoxidized to 3-benzyl-17cyclopropylmethyl-normorphinone, a novelcompound, by Swern oxidation. Using the conditions set forth in thisinvention, 3-benzyl-17-cyclopropylmethylnormorphinone is oxidized to3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone either by directlyreacting with hydrogen peroxide in formic acid or by first converting to3-benzyl-17-cyclopropylmethylnormorphinone dienol acylate, a novelcompound, and then reacting the latter with hydrogen peroxide in formicacid or a peroxyacid as set forth in the synthesis of oxycodone. Withoutisolation of 3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone fromits reaction mixture, it is hydrogenated to remove the benzyl group andreduce the 7, 8-double bond simultaneously to provide naltrexone in goodyield.

This synthesis of Naltrexone from morphine is shown below: ##STR23##

A general scheme for the synthesis of noroxymorphone from morphine canbe depicted below wherein P, Q, Q' and R" are as previously indicated.##STR24##

As hereinbefore indicated, certain intermediate compounds found duringthe synthesis of the desired end products, are themselves novelcompositions of matter. These compounds are set forth in the claims.

The following examples are illustrative of the invention.

A. Synthesis of Oxycodone From Codeine Through Codeinone Dienol Acetate

EXAMPLE 1

Preparation of codeinone (1-2)

To a solution of dimethylsulfoxide (16.53 g, 0.21 mole) in CH₂ Cl₂ (80ml) at -78° C. was added dropwise a solution of oxalyl chloride (13.01g, 0.10 mole) in CH₂ Cl₂ (50 ml) over a period of 40 min. After stirringfor 10 min., a solution of codeine (20.33 g, 0.068 mole) in CH₂ Cl₂ (100ml) was added over 50 min. while keeping the reaction mixture at -78° C.After stirring at -78° C. for 2 hr., Et₃ N (50 ml) was added, followedby CH₂ Cl₂ (100 ml). The reaction mixture was allowed to warm-up to roomtemperature, washed with water (6×150 ml), dried over anhydrous Na₂ SO₄and evaporated to dryness in vacuo to give codeinone (25.57 g). IR(KBr)(ν, cm⁻¹): 1668 (s, sharp, --C═C--C═O); NMR (δ_(H))(CDCl₃): 6.67(1, d, J, 8.2, 2-H), 6.62 (1, d, J, 10.2, 8-H), 6.59 (1, d, J, 8.2,1-H), 6.07(1, dd, J, 10.2 & 2.9,7-H), 4.68 (1,s, 5-H), 3.85(3,s, OCH₃),3.45-3.35(1, m, 9-H), 3.25-3.17 (1, m, 14-H), 3.10 (1, d, J, 18.5,10-H.sub.β), 2.61 (1, dm, J, 11.9, 16-H_(e)), 2.45 (3, s, NCH₃), 2.30(1, dd, J, 18.5 & 5.5, 10-H.sub.α), 2.30 (1, td, J, 11.9 & 3.7,16-H_(a)), 2.06 (1, td, J, 12.0 & 4.8, 15-H_(a)), 1.85 (1, dm, J, 12.5,15-H_(e)).

EXAMPLE 2

Preparation of codeinone dienol acetate (1-3)

A mixture of codeinone (5.98 g, 0.02 mole), sodium acetate (1.77 g, 0.02mole) and acetic anhydride (35.76 g, 0.35 mole) in toluene (6 ml) washeated at 90˜105° C. for 5 hr, cooled, diluted with CH₂ Cl₂ (300 ml),and basified with NaHCO₃ (66g in 300 ml of ice-cold water). The organicportion was separated, washed with water (4×150 ml), dried overanhydrous Na₂ SO₄, and evaporated to dryness in vacuo to give an oil(9.4 g), which was chromatographed on silica gel with 5% CH₃ OH in CH₂Cl₂ to give codeinone dienol acetate as brown needles (5.62 g, 83%yield), IR (KBr)(ν, cm⁻¹): 1745 (s, sharp, C═C--OAc); NMR(δ_(H))(CDCl₃): 6.67 (1, d, J, 8.1, 2-H), 6.59 (1, d, J, 8.2, 1-H), 5.79(1, dd, J, 6.3 & 1.0, 7-H), 5.57 (1, d, J, 6.3, 8-H), 5.48 (1, s, 5-H),3.85 (3, s, OCH₃), 3.66 (1, d, J, 7.0, 9-H), 3.35 (1, d, J, 18.2,10-H.sub.β), 2.90 (1, td, J, 12.8 & 3.7, 16-H_(a)), 2.74 (1, dd, J, 18.4& 7.4, 10-H.sub.α), 2.65 (1, dm, J, 13.2, 16-H_(e)), 2.48 (3, s, NCH₃),2.31 (1, td, J, 12.7 & 5.2, 15-H_(a)), 2.20 (3, s, OAc), and 1.75 (1,dm, J. 12.7, 15-H_(e)).

EXAMPLE 3

Preparation of 14-hydroxycodeinone (1-4) from codeinone dienol acetate(1-3) by H₂ O₂

A solution of codeinone dienol acetate (1.12 g, 3.3 mmol), formic acid(90% aqueous solution, 0.80 g, 15.6 mmol), hydrogen peroxide (31%aqueous solution, 0.90 g, 8.2 mmol), and water (1.60 g) was allowed tostir at 40-42° C. for 4.5 hr, cooled to room temperature, basified withconcentrated NH₄ OH, and extracted with CH₂ Cl₂ (50 ml). The extract waswashed with water (20 ml), dried over anhydrous Na₂ SO₄, and evaporatedto dryness in vacuo to give 14-hydroxycodeinone (0.80 g, 78% yield). TheR_(f) value in TLC, the IR spectrum and the NMR spectrum of the productwere comparable to those obtained from an authentic sample.

EXAMPLE 4

Preparation of 14-hydroxycodeinone (1-4) from codeinone dienol acetate(1-3) by MCPBA

A solution of codeinone dienol acetate (1.16 g, 3.4 mmol), oxalic acid(0.70 g, 7.4 mmol) and 3-chloroperoxybenzoic acid (57˜86%, 0.83 g) inglacial acetic acid (10.02 g) was allowed to stir at room temperaturefor 6 hr, basified with concentrated NH₄ OH, and extracted with CH₂ Cl₂(50 ml). The extract was washed with water (10 ml), dried over anhydrousNa₂ SO₄, and evaporated to dryness in vaco to give a crude product (1.29g), which was chromatographed on silica gel to give pure14-hydroxycodeinone (0.76 g, 72% yield). IR (KBr)(ν, cm⁻¹): 3300 (m, b,--OH), 1670 (s, sharp, C═C--C═O), NMR (δ_(H))(CDCl₃): 6.69 (1, d, J,8.2, 2-H), 6.60 (1, d, J, 8.2, 1-H), 6.60 (1, d, J, 10.1, 8-H), 6.17 (1,dd, J, 10.1 & 0.3, 7-H), 4.69 (1, s, 5-H), 3.85 (3, s, OCH₃), 3.23 (1,d, J, 18.6, 10-H.sub.β), 3.03 (1, d, J, 6.0, 9-H), 2.63-2.16 (1, m,15-H_(a)), 2.63-2.16 (2, m, 16-H_(a) & 16-He), 2.6-2.4 (1, b, --OH),2.50 (1, dd, J, 18.5 & 4.9, 10-H.sub.α), 2.45 (3, s, NCH₃), 1.68 (1, dm,J, 12.7,15-H_(e)). The R_(f) value in TLC, the IR spectrum and the NMRspectrum of the product were consistent with those obtained from anauthentic sample.

EXAMPLE 5

Preparation of 14-hydroxycodeinone (1-4) from codeinone (1-2) by H₂ O₂

A solution of codeinone (0.503 g, 1.7 mmol), formic acid (0.7 ml) and H₂O₂ (1.0 ml) in Water (1.4 ml) was allowed to stir at 50-55° C. for 7 hr.The mixture was cooled, basified with NH₄ OH, and extracted with CHCl₃(3×15 ml). The extract was washed with water, dried over anhydrous Na₂SO₄ and evaporated to dryness in vacuo to give a solid residue (0.17 g),which is comparable to 14-hydroxycodeinone in its IR spectrum, NMRspectrum, and the R_(f) value in TLC with those of an authentic sample.

EXAMPLE 6

Preparation of oxycodone (1-5) from codeinone dienol acetate (1-3)

A solution of codeinone dienol acetate (0.50 g, 1.48 mmol), formic acid(0.7 ml), hydrogen peroxide (0.43 g, 30%, 3.79 mmol), and water (1.4 ml)was heated at 43-44° C. for 6 hr and cooled to rt. over night. To thesolution was added 5% Pd/C (80 mg) and hydrogenated at rt. under 28 psiof hydrogen gas for 18 hr. The reaction mixture was filtered. Thefiltrate was basified with NH₄ OH and extracted with methylene chloride.The extract was washed with water, dried over anhydrous sodium sulfate,and evaporated in vacuo to dryness to give oxycodone (0.40 g, 85%yield). The R_(f) value in TLC and the IR spectrum of the product werecomparable to those obtained from an authentic sample.

B. Synthesis of Oxymorphone From Morphine Through 3Acetylmorphinone

EXAMPLE 7

Preparation of 3-acetylmorphine(2-1)

A mixture of morphine (23.63 g, 83 mmol), NaHCO₃ (28.2 g, 336 mmol), Ac₂O (8.69 g, 85 mmol) in toluene (500 ml) and CH₃ CN (900 ml) was heatedat reflux for 21 hrs. The reaction mixture was evaporated to dryness invacuo. To the residue was added water (80 ml) and extracted withchloroform (500 ml). The extracts were dried, combined and evaporated todryness in vacuo to obtain a residue, which was chromatographed onsilica gel (column: d=6 cm, I=8 cm, packed with 141 g of silica gel;solvent system: 5-10% MeOH in CH₂ Cl₂) to yield 3-acetylmorphine (27 g,100% yield). IR (KBr)(ν, cm⁻¹): 3500 (m, sharp, --OH), 1750 (s, sharp,AcO); NMR (δ_(H))(CDCl₃): 6.73(1, d, J, 8.1,2-H), 6.57(1, d, J, 8.1,1-H), 5.74(1, dm, J, 10.1,7-H), 5.25 (1, dm, J, 9.9, 8-H), 4.91 (1, d,J, 6.9, 5-H), 4.25-4.10 (1, m, 6-H), 3.50-3.35 (1, m, 9-H), 3.05(1, d,J, 19.1, 10-H.sub.β), 2.8-2.7 (1, m, 14-H), 2.85-2.60 (1, m, 16-H_(e)),2.50-2.25 (1, m, 16-H_(a)), 2.45 (3, s, NCH₃), 2.5-2.2 (1, m,10-H.sub.α), 2.28 (3, s, AcO), 2.06 (1, td, J, 12.1 & 5.0, 15-H_(a)),2.0-1.85 (1, m, 15-H_(e)).

EXAMPLE 8

Preparation of 3-acetylmorphinone (2-2)

To a solution of DMSO (14.42 g, 158 mmol) in CH₂ Cl₂ at -78° C. wasadded oxalyl chloride (11.68 g, 92 mmol) in CH₂ Cl₂ (50 ml) in 18 min.The solution was allowed to stir for 15 min. A solution of3-acetylmorphine (20.02 g, 61 mmol) in CH₂ Cl₂ (100 ml) was addeddropwise in one hr. The resulting mixture was allowed to stir at -78° C.for 2 hrs. Et₃ N (50 ml) was added. The reaction mixture was allowed towarm-up to rt., washed with water (4×100 ml), dried over anhydrous Na₂SO₄, and evaporated to dryness in vacuo to obtain a dark residue (25.8g), which was chromatographed on silica gel (column: d=5 cm, I=10 cm;solvent system: 5% MeOH in CHCl₃) to give 3-acetylmorphinone (14.5 g,73% yield). IR (KBr)(ν, cm⁻¹): 1760 (s, sharp, AcO), 1670 (s, sharp,C═C--C═O); NMR (δ_(H))(CDCl₃): 6.81 (1, d, J, 8.1, 2-H), 6.65 (1, d, J,8.2, 1-H), 6.62 (d, J, 10.2, 8-H), 6.08 (1, dd, J, 10.3 & 2.8, 7-H),4.73 (1, s, 5-H), 3.53-3.40 (1, m, 9-H), 3.25-3.20 (1, m, 14-H), 3.14(1, d, J, 18.9, 10-H.sub.β), 2.63 (1, dm, J, 12.1, 16-H_(e)), 2.46 (3,s, NCH₃), 2.5-2.2 (1, m, 10-H.sub.α), 2.5-2.2 (1, m, 16-H_(a)), 2.27 (3,s, AcO), 2.09 (1, td, J, 12.9 & 4.8, 15-H_(a)), 1.95-1.80 (1, m,15-H_(e)).

EXAMPLE 9

Preparation of 3-acetylmorphinone dienol acetate (2-3)

A solution of 3-acetylmorphinone (3.25 g, 10 mmol) and acetic anhydride(29.1 g) was stirred at 99° C. for 15 hr. The resulting mixture wasbasified with aqueous sodium bicarbonate, and extracted with CH₂ Cl₂.The extract was washed with water, dried over anhydrous sodium sulfate,and evaporated in vacuo to dryness. The residue (3.95 g) waschromatographed on silica gel to give 3-acetylmorphinone dienol acetate(1.5 g, 41% yield). IR (KBr)(ν, cm⁻¹): 2900 (m, sharp), 1750 (s, sharp,AcO); NMR (δ_(H))(CDCl₃): 6.78 (1, d, J, 8.1, 2-H), 6.62 (1, d, J,8.1,1-H), 5.78 (1, dd, J, 6.3 & 0.9, 7-H), 5.55 (1, d, J, 6.3, 8-H),5.50 (1, s,5-H), 3.63 (1, d, J, 6.9, 9-H), 3.34 (1, d, J, 18.3,10-H.sub.β), 2.85 (1, td, J, 12.8 & 3.6,16-H_(a)), 2.72 (1, dd, J, 18.5& 6.5, 10-H.sub.α), 2.63 (1, dm, J, 12.3, 16-H_(e)), 2.46 (3, s, NCH₃),2.28 (3, s, 3-AcO), 2.19 (3, s, 6-AcO), 2.25-2.10 (1, m, 15-H_(a)), 1.76(1, dm, J, 12.7,15-H_(e)); MS (EI), m/e (%): 367 (M⁺, 52), 325 (89,[M-CH₂ CO]⁺), 283 (68, [M-2CH₂ CO]⁺), 43 (100, [CH₃ CO]⁺).

EXAMPLE 10

Preparation of 3-acetylmorphinone dienol acetate (2-3)

A mixture of 3-acetylmorphinone (6.05 g, 18.6 mmol), NaHCO₃ (2.12 g, 26mmol), and Ac₂ O (40.3 g, 395 mmol) in toluene (110 ml) was heated at75° C. for 29 hrs. The cooled reaction mixture was chromatographed onsilica gel (column: d=5 cm, packed with 100 g of dry silica gel; solventsystems: 700 ml of CH₂ Cl₂ and then 5% MeOH in CH₂ Cl₂) to obtain3-acetylmorphinone dienol acetate (6.71 g, 99% yield). The R_(f) valuein TLC, the IR spectrum, and the NMR spectrum of the product werecomparable to those obtained from an authentic sample.

EXAMPLE 11

Preparation of 3-acetyl-14-hydroxymorphinone (2-4) from3-acetylmophinone dienol acetate (2-3) by MCPBA

A solution of 3-acetylmorphinone dienol acetate (1.42 g, 3.88 mmol),oxalic acid (0.71 g, 7.89 mmol), meta-chloroperbenzoic acid (0.63 g,57-86% pure) in AcOH was allowed to stir at rt. overnight, basitied withconc. NH₄ OH, extracted with CH₂ Cl₂ (3×70 ml). The extracts were dried,combined, and evaporated to dryness in vacuo to give a solid residue,which was chromatographed on silica gel (column: d=2 cm, packed with 28g of silica gel, eluting solvent: 5% MeOH in CH₂ Cl₂ to give3-acetyl-14-hydroxymorphinone (1.12 g, 85% yield). The R_(f) value inTLC and the IR spectrum of the product were comparable to those obtainedfrom an authentic sample.

EXAMPLE 12

Preparation of 3-acetyl-14-hydroxymorphinone (2-4) from 3-acetylmorphinedienol acetate (2-2) by H₂ O₂

A solution of 3-acetylmorphinone dienol acetate (1.5 g, 4.1 mmol),formic acid (10 ml), water (0.5 ml), and hydrogen peroxide (0.55 ml,30%, 4.8 mmol) was stirred at 40-47° C. for 5.5 hr. The reactionsolution was basified with sodium carbonate (12 g, 115 mmol) andextracted with CH₂ Cl₂ (3×40 ml). The combined extract was dried overanhydrous sodium sulfate and evaporated in vacuo to dryness. The residue(1.06 g) was chromatographed on silica gel to give3-acetyl-14-hydroxymorphinone (0.75 g, 57% yield). IR (KBr)(ν, cm⁻¹):3300 (m, b, --OH), 2900 (m, sharp), 1757 (s, sharp, 3-AcO), 1670 (s,sharp, C═C--C═O); NMR (δ_(H))(CDCl₃): 6.82 (1, d, J, 8.2, 2-H), 6.67 (1,dd, J, 8.2 & 0.9, 1-H), 6.61 (1, dd, J, 10.0 & 0.7, 8-H), 6.18 (1, dd,J, 10.0 & 0.3, 7-H), 5.22-3.82 (1, b, --OH), 4.73 (1, s, 5-H), 3.26 (1,d, J, 18.9, 10-H.sub.β), 3.05 (1, d, J, 6.0, 9-H), 2.66-2.20 (2, m,16-H_(a) & 16-H_(e)), 2.66-2.20 (1, m, 15-H_(a)), 2.56 (1, dd, J, 19.7 &6.0, 10-H.sub.α) 2.45 (3, s, NCH₃), 2.26 (3, s, -A_(c) O), 1.72 (1, dm,J, 13.1, 15-H_(e)); MS (EI), m/e (%): 341 (M⁺, 54), 299 (67, [M-CH₂CO]⁺), 70 (100, [CH₂ ═CH--CH═CH--OH]⁺).

EXAMPLE 13

Preparation of 3-acetyloxymorphone (2-5)

A mixture of 3-acetyl-14-hydroxymorphinone (0.34 g, 1 mmol) and Pd-C(5%, 0.8 g) in ethanol (50 ml) was hydrogenated in a Parr hydrogenatorwith hydrogen gas (28) at rt. for 3 hr. The reaction mixture wasfiltered through celite. The filtrate was evaporated in vacuo to give3-acetyloxymorphone (0.28 g, 82% yield). IR (KBr)(ν, cm⁻¹): 3400 (s, b,--OH), 2900 (m, sharp), 1760 (s, sharp, AcO), 1720 (s, sharp, C═O); NMR(δ_(H))(CDCl₃): 6.86 (1, d, J, 8.2, 2-H), 6.68 (1, d, J, 8.2,1-H), 5.29(1, s, b, --OH), 4.67 (1, s, 5-H), 3.19 (1, d, J, 18.9, 10-H.sub.β),3.01 (1, dd, J, 14.6 & 5.3, 7-H_(a)) 2.92 (1, d, J, 5.5, 9-H), 2.59 (1,dd, J, 18.9 & 6.0, 10-H.sub.α), 2.42 (3, s, NCH₃), 2.60-2.15 (1, m,7-H_(e)), 2.60-2.15 (1, m, 15-H_(a)), 2.60-2.15 (2, m, 16-H_(a) &16-H_(e)), 2.30 (3, s, AcO), 1.88 (1, ddd, J, 13.3, 5.2 & 3.0, 8-H_(e)),1.62 (1, td, J, 13.8 & 3.6, 8-H_(a)), 1.57 (1, dm J, 13.4, 15-H_(e)); MS(EI), m/e (%): 343 (M⁺, 1.6), 301 (100, [M-CH₂ CO]⁺), 70 (57, [CH₂═CH--CH═CH--OH]⁺).

EXAMPLE 14

Preparation of oxymorphone from 3-acetyloxymorphone (2-6)

A solution of 3-acetyloxymorphone (0.18 g, 0.52 mmol) and sodiumcarbonate (0.13 g, 1.2 mmol) in methanol (5 ml) and water (0.7 ml) wasstirred at rt. for 4 hr. The reaction mixture was evaporated in vacuo toremove methanol, added water (20 ml) and extracted with chloroform (4×20ml). The combined extract was dried over anhydrous sodium sulfate, andevaporated in vacuo to dryness to give oxymorphone (0.127 g, 85% yield).IR (KBr)(ν, cm⁻¹): 3340 (m, b, --OH), 2900 (m, sharp), 1715 (s, sharp,C═O); NMR (δ_(H))(CDCl₃): 6.71 (1, d, J, 8.2, 2-H), 6.59 (1, d, J,8.2,1-H), 5.55-4.10 (2, b, --OH), 4.67 (1, s, 5-H.sub.β), 3.14 (1, d, J,18.8, 10-H), 3.04 (1, td, J, 14.4 & 5.3, 7-H_(a)), 2.86 (1, d, J, 5.8,9-H), 2.60-2.15 (1, m, 7-H_(e)), 2.60-2.15 (2, m, 16-H_(a) 16-H_(a)),2.52 (1, dd, J, 18.2 & 5.8, 10-H.sub.α), 2.50-2.15 (1, m, 15-H_(a)),2.40 (3, s, NCH₃), 1.87 (1, ddd, J, 13.4, 5.1 & 2.8, 8-H_(e)), 1.62 (1,td, J, 13.9 & 3.5, 8-H_(a)), 1.58 (1, dm, J, 13.4,15-H_(e)).

C. Synthesis of Oxymorphone From Morphine Through 3-Benzylmorphinone

EXAMPLE 15

Preparation of 3-benzylmorphine (3-1)

A solution of morphine (14.27 g, 50.0 mmol), NaOH (2.04 g, 51.0 mmol),and benzylbromide (8.47 g, 49.5 mmol) in MeOH (150 ml) and water (50 ml)was stirred at rt. for 3.5 hr., evaporated in vacuo to remove MeOH. Theresidue was extracted with CH₂ Cl₂ (120 ml). The extract was dried overanhydrous Na₂ SO₄ and evaporated in vacuo to dryness to give a cruderesidue, which was chromatographed on silica gel (column: d=6.5 cm,I=10.5 cm; eluting solvent: 15% MeOH in CH₂ Cl₂) to obtain3-benzylmorphine (13.1 g, 70% yield). The R_(f) value in TLC and the IRspectrum of the product were comparable to those obtained from anauthentic sample.

EXAMPLE 16

Preparation of 3-benzylmorphinone (3-2) by Swern oxidation

To a solution of dimethyl sulfoxide (3.75 g, 48 mmol) in CH₂ Cl₂ (15 ml)at -78° C., was added a solution of oxalyl chloride (3.8 g, 30 mmol) inCH₂ Cl₂ (5 ml) in 20 min. It was allowed to stir for another 20 min. Tothis solution at -78° C., was added a solution of 3-benzylmorphine (6.0g, 16 mmol) in CH₂ Cl₂ (15 ml) in 45 min. Then, the reaction mixture wasstirred at -78° C. for 3 hr., added triethylamine (17 ml), warmed up tort., washed with water (8×100 ml), dried over anhydrous sodium sulfate,and evaporated in vacuo to dryness to give 3-benzylmorphinone (about 65%yield). The R_(f) value in TLC and the IR spectrum of the product werecomparable to those obtained from an authentic sample.

EXAMPLE 17

Preparation of 3-benzylmorphinone dienol acetate (3-3)

A mixture of 3-benzylmorphinone (6.0 g, 16.1 mmol), acetic anhydride(47.5 g, 466 mmol), sodium acetate (2.65 g), sodium carbonate (5.2 g),and DMAP(about 0.3 g) was heated at 95° C. for 17 hr., basified withaqueous sodium bicarbonate solution to pH 9.0, and extracted with CH₂Cl₂. The extract was washed with water, dried over anhydrous sodiumsulfate, evaporated off the solvent in vacuo to give a crude product (9g), which was chromatographed on silica gel to obtain 3-benzylmorphinonedienol acetate (2.6 g, 39% yield). IR (KBr)(ν, cm⁻¹): 2900 (m, sharp),1750 (s, sharp, C═C--C═C--OAc); NMR (δ_(H))(CDCl₃): 7.53-7.15 (5, m,--C₆ H₅), 6.69 (1, d, J, 8.2, 2-H), 6.53 (1, d, J, 8.2,1-H), 5.79 (1,dd, J, 6.2 & 0.9,7-H), 5.58 (1, d, J, 6.4, 8-H), 5.49 (1, s, 5-H), 5.14(2, s, OCH₂ Ph), 3.70 (1, d, J, 7.0,9-H), 3.33 (1, d, J, 18.1,10-H.sub.β), 2.93 (1, td, J, 12.9 & 3.7,16-H_(a)), 2.76 (1, dd, J, 18.5& 6.7, 10-H.sub.α), 2.68 (1, dm, J, 13.5, 16-H_(e)), 2.49 (3, s, NCH₃),2.32 (1, td, J, 12.8 & 5.1,15-H_(a)), 2.18 (3, s, AcO), 1.74 (1, dm, J,12.8, 15-H_(e)); MS (EI), m/e (%): 415 (M⁺, 15), 324 (40, [M-CH₂ Ph]⁺),282 (48, [M-CH₂ Ph-CH₂ CO]⁺), 91 (100, [CH₂ Ph]⁺).

EXAMPLE 18

Preparation of 3-benzyl-14 hydroxymorphinone (3-4) from3-benzylmorphinone dienol acetate (3-3) by MCPBA in HOAc

A solution of 3-benzylmorphinone dienol acetate (2.6 g, 6.26 mmol),oxalic acid (1.15 g, 12.8 mmol), and 3-chloroperbenzoic acid (1.85 g,57-86%) in glacial acetic acid(20 ml) was stirred at rt. for 15.5 hr.,basified with aqueous sodium bicarbonate solution to pH 9, extractedwith CH₂ Cl₂. The extract was washed with water, dried over anhydroussodium sulfate, and evaporated in vacuo to dryness to obtain a crudeproduct (2.3 g), which was chromatographed on silica gel to give3-benzyl-14-hydroxymorphinone (1.43 g, 59% yield). IR (KBr)(ν, cm⁻¹):3280 (m, b, OH), 2900 (m sharp), 1670 (s, sharp, C═C--C═O); NMR(δ_(H))(CDCl₃): 7.44-7.20 (5, m, --C₆ H₅), 6.71 (1, d, J, 8.1, 2-H),6.59 (1, d, J, 10.1, 8-H), 6.55 (1, d, J, 8.2, 1-H), 6.16 (1, dd, J,10.1 & 0.5, 7-H), 5.16 (2, s, OCH₂ Ph), 4.71 (1, s, 5-H), 3.20 (1, d, J,18.6, 10-H.sub.β), 3.02 (1, d, J, 6.0, 9-H), 2.70-2.40 (1, b, --OH),2.60-2.35 (2, m, 16-H_(a) & 16-H_(e)), 2.53 (1, dd, J, 19.4 & 6.0,10-H.sub.α), 2.5-2.2 (1, m, 15-H_(a)), 2.43 (3, s, NCH₃); 1.67 (1, dm,J, 12.7, 15-H_(e)).

EXAMPLE 19

Preparation of 3-benzyl-14 hydroxymorphinone (3-4) from3-benzylmorphinone dienol acetate (3-3) by H₂ O₂ in formic acid andwater

A solution of 3-benzylmorphinone dienol acetate (1.4 g, 3.37 mmol),formic acid (10 ml, 90%), and hydrogen peroxide (0.48 ml, 30%, 4.2 mmol)was stirred at 38˜47° C. for 4 hr., basified with sodium carbonate to pH8, extracted with CH₂ Cl₂. The extract was washed with aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate, andevaporated in vacuo to dryness. The residue (1.0 g) was chromatographedon silica gel to give 3-benzyl-14 hydroxymorphinone (0.7 g, 54% yield).The R_(f) value in TLC and the IR spectrum of the product werecomparable to those obtained from an authentic sample.

EXAMPLE 20

Preparation of oxymorphone (3-5) from 3-benzyl-14 hydroxymorphinone(3-4)

A mixture of 3-benzyl-14-hydroxymorphinone (0.9 g, 2.31 mmol) and 5%Pd-C (0.65 g) in ethanol (50 ml) was hydrogenated in a Parr hydrogenatorwith hydrogen gas (30 psi) at rt. for 4 hr., and filtered throughcelite. The filtrate was evaporated in vacuo to give oxymorphone (0.65g, 94% yield). IR (KBr)(ν, cm⁻¹): 3200 (s, b, --OH), 2920 (m, sharp),1720 (s, sharp, C═O); NMR (δ_(H))(CDCl₃): 6.72 (1, d, J, 8.1, 2-H), 6.58(1, d, J, 8.2, 1-H), 5.38 (2, b, --OH), 4.70 (1, s, 5-H), 3.15 (1, d, J,18.6, 10-H.sub.β), 3.04 (1, td, J, 14.5 & 5.3, 7-H_(a)), 2.88 (1, d, J,5.8, 9-H), 2.54 (1, dd, J, 19.6 & 5.7, 10-H.sub.α), 2.55-2.15 (2, m,16-H_(a) & 16-H_(e)), 2.45-2.15 (2, m, 15-H_(a) & 7H_(e)), 2.41 (3, s,NCH₃), 1.88 (1, ddd, J, 13.3, 5.2 & 3.0, 8-H_(e)), 1.67 (1, td, J, 14.4& 3.5, 8-H_(a)), 1.73-1.50 (1, m, 15-H_(e)).

Synthesis of Noroxymorphone From Morphine Through3,17-Dibenzylnormorphine

EXAMPLE 21

Preparation of 3-benzylmorphine (4-1) (see also 3-1))

To a suspension of morphine (10.0 g, 35.1 mmol) in THF (200 ml), wasadded benzyl bromide (5.5 ml, 98%, 45.3 mmol) and sodium hydroxide (1.48g, 37.0 mmol) at 0° C. The reaction mixture was stirred overnight. Thereaction temperature rose gradually to rt. during the process. THF inthe reaction mixture was removed on a rotary evaporator. The residue wasdissolved in CH₂ Cl₂ (150 ml) and water (50 ml). The organic layer wasseparated. The aqueous layer was extracted with CH₂ Cl₂ (3×50 ml). Thecombined organic layer was dried over anhydrous sodium sulfate,evaporated in vacuo to obtain a crude product (13 g), which wasdissolved in CH₂ Cl₂ and loaded onto a silica gel column (3×30 cm). Thecolumn was first eluted with 3% methanol in CH₂ Cl₂, followed by 5%methanol in CH₂ Cl₂. Pure fractions were combined to obtain3-benzylmorphine (7.9 g, 60% yield). IR (KBr)(ν, cm⁻¹): 3540 (m, sharp,--OH), 3020 (m, sharp), 2900 (s, sharp), 1600 (m, sharp); NMR(β_(H))(CDCl₃): 7.50-7.20 (5, m, --C₆ H₅), 6.70(1, d, J, 8.1,2-H), 6.51(1, dd, J, 8.1 & 0.9,1-H), 5.65(1, dm, J, 9.9,7-H), 5.26(1, dt, J, 9.9 &2.5, 8-H), 5.12 (2, AB, OCH₂ Ph), 4.85 (1, dd, J, 6.6 & 1.2, 5-H),4.22-4.05 (1, m, 6-H), 3.32 (1, dd, J, 6.2 & 3.3, 9-H), 3.02 (1, d, J,18.6, 10-H.sub.β), 2.75-2.65 (1, m, 14-H), 2.75-2.65 (1, b, --OH), 2.58(1, dm, J, 12.0,16-H_(e)), 2.5-2.3 (1, m, 16-H_(a)), 2.42 (3, s, N-CH₃),2.27 (1, dd, J, 18.6 & 6.6, 10-H.sub.α), 2.05 (1, td, J, 12.1 &5.3,15-H_(a)), 1.85 (1, dm, J, 12.5, 15-H_(e)).

EXAMPLE 22

Preparation of 6-acetyl-3-benzylmorphine (4-2)

To a solution of 3-benzylmorphine (12.7 g, 33.9 mmol) in CH₂ Cl₂ (300ml), was added triethylamine (10 ml, 99%, 71.2 mmol), acetic anhydride(7.5 ml, 99%, 78.6 mmol), and 4-dimethylaminopyridine (0.3 g). Thereaction mixture was heated under reflux for 2 hr, cooled with anice--H₂ O bath, then transferred to a separatory funnel, and washed withcold 10% aqueous NaHCO₃ solution (3×100 ml). The organic layer wasseparated and dried over anhydrous Na₂ SO₄. Removal of solvent gave6-acetyl-3-benzylmorphine (13.87 g, 96% yield). IR (KBr)(ν, cm⁻¹): 2900(m, sharp), 1727 (s, sharp, AcO); NMR (β_(H))(CDCl₃): 7.47-7.20 (5, m,--C₆ H₅), 6.68 (1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2,1-H), 5.63(1, dm,J, 10.1,7-H), 5.43(1, dt, J, 10.1 & 2.3, 8-H), 5.25-5.15(1, m, 6-H),5.14 (2, s, --OCH₂ Ph), 5.10 (1, dd, J, 6.7 & 1.1, 5-H), 3.34 (1, dd, J,6.0 & 3.3, 9-H), 3.01 (1, d, J, 18.6, 10-H.sub.β), 2.79-2.70 (1, m,14-H), 2.59(1, dd, J, 12.1 & 3.4, 16-H_(e)), 2.43 (3, s, N-CH₃), 2.37(1, td, J, 11.8 & 3.6,16-H_(a)), 2.27 (1, dd, J, 18.8 & 6.6,10-H.sub.α), 2.10 (3, s, AcO), 2.04 (1, td, J, 11.9 & 5.1, 15-H_(a)),1.86 (1, dm, J, 12.5, 15-H_(e)).

EXAMPLE 23

Preparation of 3,17-dibenzylnormorphine (4-4) from6-acetyl-3-benzylmorphine

To a solution of 6-acetyl-3-benzylmorphine (13.7 g, 32.1 mmol) andproton sponge (1.2 g) in 1,2-dichloroethane (50 ml) was added1-chloroethyl chloroformate (ACE-Cl, 4.5 ml, 41.7 mmol) at 0° C. Thereaction mixture was heated under reflux for 30 min. The reactionmixture was cooled to rt., added methanol (30 ml) and conc. HCl (a fewdrops), and heated under reflux for another 30 min. Precipitate cameout. Then, methanol (50 ml), Na₂ CO₃ (10.2 g, 96.2 mmol) and benzylbromide (4.7 ml, 98%, 38.7 mmol) were added at rt. The reaction mixturewas stirred at rt. over the weekend. The solvents were removed on arotary evaporator. Ethyl acetate (100 ml) and water (100 ml) was added.The organic layer was separated and washed with 10% aqueous NaHCO₃solution (2×50 ml), then dried over anhydrous Na₂ SO₄. Removal ofsolvent gave a crude product (7.5 g), which was dissolved in CH₂ Cl₂ andloaded onto a column (5×16 cm, packed with silica gel in CH₂ Cl₂). Thecolumn was eluted first with CH₂ Cl₂ and then with CH₂ Cl₂ /EtOAc(50/50) to give 3,17-dibenzylnormorphine (13.3 g, 92% yield from6-acetyl-3-benzylmorphine). IR (KBr)(ν, cm⁻¹): 3440 (m, b, --OH), 3020(m, sharp), 2900 (m, sharp), 1600 (m, sharp); NMR (δ_(H))(CDCl3):7.50-7.20 (10, m, --C₆ H₅); 6.70 (1, d, J, 8.2, 2-H), 6.52 (1, d, J,8.1, 1-H), 5.58 (1, dm, J, 9.9, 7-H), 5.21 (1, dm, J, 9.9, 8-H), 5.12(2, AB, --OCH₂ Ph), 4.85 (1, dd, J, 6.4 & 1.2, 5-H), 4.25-4.05 (1, m,6-H), 3.69 (2, AB, N-CH₂ Ph), 3.37 (1, dd, J, 6.2 & 3.3, 9-H), 3.06 (1,d, J, 18.6, 10-H.sub.β), 2.80-2.55 (1, b, --OH), 2.75-2.65 (1, m, 14-H),2.61 (1, dd, J, 12.1 & 4.0, 16-H_(e)), 2.46 (1, td, J, 11.9 &3.7,16-H_(a)), 2.29 (1, dd, J, 18.6 & 6.4, 10-H.sub.α), 2.04 (1, td, J,11.7 & 5.3, 15-H_(a)), 1.86 (1, dm, J, 12.5, 15-H_(e)).

EXAMPLE 24

Preparation of 3,17-dibenzylnormorphinone (4-5)

To a solution of DMSO (5.87 g, 75.1 mmol) in CH₂ Cl₂ (40 ml) at -78° C.,was added a solution of oxalyl chloride (4.7 g, 37.6 mmol) in CH₂ Cl₂(15 ml) in 20 min. The mixture was stirred for 10 min. and then wasadded a solution of 3,17-dibenzylnormorphine (11.3 g, 25.1 mmol) in CH₂Cl₂ (20 ml) in 40 min. The mixture was stirred at -78° C. for 2 hr, andthen Et₃ N (13 ml) was added. It was allowed to warm up to rt.,transferred to a separatory funnel, washed with water (10×100 ml), driedover anhydrous sodium sulfate, and evaporated in vacuo to dryness togive 3,17-dibenzylnormorphinone (11.0 g, 98% yield). IR (KBr)(ν, cm⁻¹):3020 (m, sharp), 2900 (m, sharp), 1670 (s, sharp, --C═C--C═O); NMR(δ_(H))(CDCl₃): 7.51-7.16 (10, m, --C₆ H₅), 6.71 (1, d, J, 8.2, 2-H),6.56 (1, d, J, 8.2, 1-H), 6.56 (1, d, J, 10.5, 8-H), 6.05 (1, dd, J,10.2 & 2.9, 7-H), 5.17 (2, s, OCH₂ Ph), 4.70 (1, s, 5-H), 3.71 (2, AB,NCH₂ Ph), 3.43 (1, dd, J, 5.2 & 3.1, 9-H), 3.23 (1, dd, J, 5.1 & 2.6,14-H), 3.12 (1, d, J, 18.5, 10-H.sub.β), 2.64 (1, dm, J, 11.8,16-H_(e)), 2.50-2.25 (1, m, 10-H.sub.α), 2.35 (1, td, J, 11.9 & 3.7,16-H_(a)), 2.05 (1, td, J, 12.0 & 4.9, 15-H_(a)), 1.81 (1, dm, J, 12.1,15-H_(e)); MS (EI), m/e (%): 449 (M⁺, 5.5), 358 (21, [M-CH₂ Ph]⁺), 91(100, [CH₂ Ph]⁺).

EXAMPLE 25

Preparation of 3,17-dibenzylnormorphinone dienol acetate (4-6)

To a mixture of 3,17-dibenzylnormorphinone (3.7 g, 8.2 mmol), CH₃ CO₂ Na(2.7 g, 32.9 mmol) and Na₂ CO₃ (10.4 g, 124 mmol), was added Ac₂ O (26.3g, 25.8 mmol). The mixture was stirred at 100° C. for 14 hr., cooled,basified to pH 8 with cold aqueous NaHCO₃, and extracted with CH₂ Cl₂(50 ml). The extract was washed with water (2×100 ml),dried overanhydrous sodium sulfate, evaporated in vacuo to give a crude product(4.6 g), which was dissolved in CH₂ Cl₂ and loaded onto a column (2.4×37cm, 77 g silica gel, packed in CH₂ Cl₂). The column was eluted with CH₂Cl₂, and then with a gradient solution of ethyl acetate in hexane toobtain pure 3,17-dibenzylnormorphinone dienol acetate (1.7 g, 42%yield). IR (KBr)(ν, cm⁻¹): 3020 (m, sharp), 2900 (m, sharp), 1750 (s,sharp, --C═C--C═C--OAc); NMR (δ_(H))(CDCl₃): 7.50-7.20 (10, m, --C₆ H₅),6.68 (1, d, J, 8.2, 2-H), 6.53 (1, d, J, 8.2,1-H), 5.77 (1, dd, J, 6.2 &0.8, 7-H), 5.47 (1, d, J, 7.3, 8-H), 5.49 (1, s, 5-H), 5.14 (2, s, OCH₂Ph), 3.75 (2, s, NCH₂ Ph), 3.64 (1, d, J, 7.0, 9-H), 3.32 (1, d, J,18.0, 10-H.sub.β), 2.95 (1, td, J, 13.0 & 3.5, 16-H_(a)), 2.75-2.60 (1,m, 16-H_(e)), 2.74 (1, dd, J, 18.7 & 7.1, 10-H.sub.α), 2.34 (1, td, J,12.6 & 4.9, 15-H_(e)), 2.17 (3, s, AcO), 1.70 (1, dm, J, 12.8,15-H_(e));MS (EI), m/e (%): 491 (M⁺, 2.9), 400 (8, [M-CH₂ Ph]⁺), 458 (10, [M-CH₂Ph-CH₂ CO]⁺), 91 (100, [CH₂ Ph]⁺).

EXAMPLE 26

Preparation of 3,17-dibenzyl-14-hydroxynormorphinone (4-7) from3,17-dibenzylnormorphinone dienol acetate (4-6) by MCPBA in HOAc

To a solution of 3,17-dibenzylnormorphinone dienol acetate (1.4 g, 2.85mmol) in glacial acetic acid (10 ml) was added oxalic acid (0.5 g, 5.6mmol) and 3-chloroperbenzoic acid (MCPBA, 0.98 g, 57˜86%). The reactionmixture was stirred at rt. for 5 hr., basified to pH 8˜9 with NH₄ OH,extracted with CH₂ Cl₂ (3×50 ml). The combined organic extract was driedover anhydrous sodium sulfate, evaporated in vacuo to dryness to obtain3,17-dibenzyl-14-hydroxynormorphinone (0.9 g, 68% yield). The R_(f)value in TLC and the IR spectrum of the product were comparable to thoseobtained from an authentic sample.

EXAMPLE 27

Preparation of 3,17-dibenzyl-14-hydroxynormorphinone (4-7) from3,17-dibenzylnormorphinone dienol acetate (4-6) by MCPBA in 90% formicacid

To a solution of 3,17-dibenzylnormorphinone dienol acetate (1.54 g, 3.13mmol) in formic acid (20 ml, 90%), was added 3-chloroperbenzoic acid(MCPBA, 1.02 g, 57-86%). The reaction mixture was stirred at rt. for 17hr., basified to pH 8 with cold aqueous Na₂ CO₃, and extracted with CH₂Cl₂. The extract was dried over anhydrous Na₂ SO₄, and evaporated invacuo to dryness. The residue was chromatographed on silica gel to give3,17-dibenzyl-14-hydroxynormorphinone (0.86 g, 60% yield). The R_(f)value in TLC and the IR spectrum of the product were comparable to thoseobtained from an authentic sample.

EXAMPLE 28

Preparation of 3,17-dibenzyl-14-hydroxynormorphinone (4-7) from3,17-dibenzylnormorphinone dienol acetate (4-6) by H₂ O₂ in formic acidand water

A solution of 3,17-dibenzylnormorphinone dienol acetate (1.7 g, 3.46mmol) and H₂ O₂ (30%, 0.5 ml) in formic acid (90%, 20 ml) was stirred at37˜47° C. for 4 hr., basified to pH 8.0 with NaHCO₃ and 5% NaHCO₃solution, extracted with CH₂ Cl₂. The extract was washed with 5% NaHCO₃,dried over anhydrous Na₂ SO₄, and evaporated in vacuo to obtain a crudeproduct, which was chromatographed on silica gel to give pure3,17-dibenzyl-14-hydroxynormorphinone (0.74 g, 60% yield). IR (KBr)(ν,cm⁻¹): R_(f) 3340 (s, b, --OH), 2900 (m, sharp), 1675 (s, sharp,--C═C--C═O); NMR (δ_(H))(CDCl₃): 7.48-7.15 (10, m, --C₆ H₅), 6.73(1, d,J, 8.2,2-H), 6.58(1, d, J, 8.8, 1-H), 6.53(1, d, J, 10.1, 8-H), 6.14 (1,d, J, 10.1, 7-H), 5.3-4.8 (1, b, --OH), 5.16 (2, s, OCH₂ Ph), 4.71 (1,s, 5-H), 3.70 (2, s, NCH₂ Ph), 3.27 (1, d, J, 18.6, 10-H.sub.β), 3.11(1, d, J, 5.8, 9-H), 2.70-2.55 (1, m, 16-H_(e)), 2.57 (1, dd, J, 18.5 &5.7, 10-H.sub.α), 2.45-2.25 (2, m, 15-H_(a) & 16-H_(a)), 1.68 (1, dm, J,11.6, 15-H_(e)); MS (El), m/e (%): 465 (M⁺, 10), 374 (20, [M-CH₂ Ph]⁺),91 (100, [CH₂ Ph]⁺).

EXAMPLE 29

Preparation of 3,17-dibenzyl-14-hydroxynormorphinone (4-7) from3,17-dibenzylnormorphinone (4-5)

A solution of 3,17-dibenzylnormorphinone (0.875 g, 2.22 mmol), H₂ O₂(30%, 0.76 ml), and formic acid (90%, 0.7 ml) in water (0.8 ml) andEtOAc (0.7 ml) was stirred at 41° C. for 7 hr., basified to pH 10 withNa₂ CO₃ and extracted with CH₂ Cl₂.(3×20 ml) The combined extract waswashed with water, dried over anhydrous Na₂ SO₄, and evaporated in vacuoto obtain 3,17-dibenzyl-14-hydroxynormorphinone (0.48 g, 53% yield). TheR_(f) value in TLC and the IR spectrum of the product were comparable tothose obtained from an authentic sample.

EXAMPLE 30

Preparation of noroxymorphone hydrochloride (4-8) from3,17-dibenzyl-14-hydroxynormorphinone (4-7)

A mixture of 3,17-dibenzyl-14-hydroxynormorphinone (1.48 g, 35.9 mmol),5% Pd-C (1.0 g), and conc. HC; (0.5 ml) in ethanol (100 ml) washydrogenated with a Parr hydrogenator with hydrogen gas (30 PSIG) at rt.for 47 hr., and filtered through celite. The filtrate was evaporated invacuo to give noroxymorphone hydrochloride (1.05 g, 100% yield). IR(KBr)(ν, cm⁻¹): 3300 (s, b, --OH, --NH), 2900 (m, sharp), 2430 (m,sharp, NH.HCl), 1710 (s, sharp, C═O); NMR (δ_(H))(CDCl₃): 10.4-8.0 (2,b, ⁺ NH₂ Cl⁻), 9.40 (1, s, --OH), 6.69 (1, d, J, 8.1, 2-H), 6.61 (1, d,J, 8.1, 1-H), 6.50 (1, s, --OH), 4.93 (1, s, 5-H), 3.70 (1,d, J,5.5,9-H), 3.33 (1, d, J, 19.1, 10-H.sub.β), 3.15-2.85 (1, m, 7-H_(a)),3.15-2.85 (2, m, 16-H_(a) & 1.6-H_(e)), 2.75-2.24 (1, m, 10-H.sub.α),2.75-2.24 (1, m, 15-H_(a)), 2.10 (1, dm, J, 14.6, 7-H_(e)), 1.96 (1, dm,J, 11.8, 15-H_(e)), 1.64-1.20 (2, m, 8-H_(a) & 8-H_(e)).

Synthesis of naltrexone from codeine through17-cyclopropylmethylnorcodeinone and 3-methylnaltrexone

EXAMPLE 31

Preparation of 6-acetylcodeine (5-2)

A solution of codeine (30 g, 100.2 mmol), acetic anhydride (18.4 g,180.2 mmol), triethylamine (18.25 g, 180.2 mmol) and4-dimethylaminopyridine (0.5 g) in dry ethyl acetate (620 ml) wasstirred at rt. under nitrogen for 12 hr, added saturated aqueous sodiumbicarbonate solution until no acetic anhydride detected. The organicportion was separated, washed with water (3×120 ml), dried overanhydrous sodium sulfate, and evaporated in vacuo to dryness to give6-acetylcodeine as white solids (34.0 g, 99% yield). IR (KBr)(ν, cm⁻¹):1725 (st, sharp, 3-AcO); NMR (δ_(H))(CDCl₃): 6.66 (1, d, J, 8.2, 2-H),6.53 (1, d, J,8.2, 1-H), 5.63 (1, ddd, J, 10.0, 2.4 & 1.0, 7-H), 5.42(1, dt, J, 9.9 & 2.3, 8-H), 5.22-5.51 (1, m, 6-H), 5.06 (dd, J, 6.7 &1.0, 5-H), 3.85 (3, s, 3-OCH₃), 3.39 (1, dd, J, 6.0 & 3.3, 9-H), 3.03(1, d, J_(jem), 18.6, 10-H.sub.β), 2.78 (1, dd, J, 5.2 & 2.6, 14-H),2.63 (1, dd, J, 11.9 & 4.6, 16-H_(a)), 2.45 (3, s, N-CH₃), 2.40 (1, td,J, 12.0 & 3.8, 16-H_(e)), 2.33 (1, dd, J, 18.5 & 6.0, 10-H.sub.α), 2.15(3, s, 6-OAc), 2.06 (1, td, J, 12.0 & 5.0, 15-H_(a)) and 1.85 (1, dm, J,12.0, 15-H_(e)).

EXAMPLE 32

Preparation of 6-acetylnorcodeine hydrochloride (5-3a)

A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethylchloroformate (5.51 g,37.8 mmol), and proton sponge (1.0 g) in methylenechloride (80 ml) was heated at reflux for 80 min. The reaction mixturewas evaporated in vacuo to dryness. The residue was chromatographed onsilica gel with ethyl acetate to give6-acetyl-17-(1-chloroethoxycarbonyl)norcodeine as an oil (12.13 g),which was dissolved in methanol with a few drops of conc. HCl. Thesolution was heated at reflux for 1 hr and evaporated in vacuo to almostdryness. The residue was added hexane and filtered to give6-acetylnorcodeine hydrochloride (10.7 g, 100% yield). IR (KBr)(ν,cm⁻¹): 3540 (NH), 1730 (st, sharp, 6-AcO), 2800-2600 (broad) and 2470(sharp)(NH.HCl); NMR (δ_(H))(DMSO-d₆): 9.69 (2, s (broad), 17-N⁺ H₂Cl⁻), 6.76 (1, d, J, 8.2, 2-H), 6.63 (1, d, J, 8.2,1-H), 5.65 (1, dd, J,10.1 & 1.8, 7-H), 5.51 (1, dt, J, 10.1 & 2.0, 8-H), 5.16 (1, dt, J, 6.7& 2.0, 6-H), 5.09 (1, dd, J, 6.7 & 0.8, 5-H), 4.20 (1, dd, J, 5.8 & 3.2,9-H), 3.77 (3, s, 3-OCH₃), 3.28-3.14 (1, m, 16-H_(e)), 3.23 (1, d, J,18.3, 10-H.sub.β), 3.07 (1, m), 14-H), 2.88 (1, dd, J, 19.2 & 6.3,10-H.sub.α), 2.73 (1, dd, J, 13.3 & 4.0, 16-H_(a)), 2.24 (1, td, J, 13.4& 4.6, 15-H_(a)), 2.07 (3, s, 6-AcO) and 1.88 (1, dm, J, 13.4,15-H_(e)).

EXAMPLE 33

Preparation of norcodeine hydrochloride (5-3b)

A solution of 6-acetylcodeine (10.0 g, 29.3 mmol), 1-chloroethylchloroformate (5.56 g,38.1 mmol), and proton sponge (1.0 g) in methylenechloride (50 ml) was heated at reflux for 50 min. The reaction mixturewas evaporated in vacuo to about 30 ml. Methanol (25 ml) andconcentrated HCl (2 ml) were added. The solution was heated at refluxfor 40 min. and evaporated in vacuo to almost dryness. The residue wasadded hexane and filtered to give norcodeine hydrochloride (8.8 g, 93%yield). IR (KBr), (ν, cm⁻¹): 3540 (NH), 3380 (6-OH), 2800-2600 (broad)and 2480 (sharp) (NH.HCl); NMR (δ_(H))(DMSO-d₆): 9.66 (2, s (broad),17-N⁺ H₂ Cl⁻), 6.72 (1, d, J, 8.2, 2-H), 6.57 (1, d, J, 8.2, 1-H), 5.66(1, dt, J, 9.9 & 3.0, 7-H), 5.28 (1, dt, J, 9.8 & 3.0, 8-H), 5.10 (1, s(broad), 6-OH), 4.82 (1, dd, J, 6.1 & 1.2, 5-H), 4.15 (2, m, 6-H & 9.7)3.77 (3, s, 3-OCH₃), 3.22 (1, d, J, 19.1, 10-H.sub.β), 3.21 (1, td, J,13.2 & 4.1, 16-H_(e)), 3.06 (1, m, 14-H), 2.91 (1, dd, J, 18.5 & 6.3,10-H.sub.α), 2.79 (1, dd, J, 13.0 & 3.9, 16-H_(a)), 2.22 (1, td, J, 13.4& 4.9, 15-H_(a)) and 1.89 (1, dd, J, 13.6 & 2.7, 15-H_(e)).

EXAMPLE 34

Preparation of 17-cyclopropylmethylnorcodeine (5-4)

A mixture of norcodeine hydrochloride (11.48 g, 27.8 mmol),(chloromethyl)-cyclopropane (5.14 g, 55.6 mmol), sodium carbonate (14.73g, 139.0 mmol), and potassium iodide (4.61 g, 27.8 mmol) in ethanol (250ml) was heated at reflux for 20 hr, cooled, and evaporated in vacuo todryness. The residue was basified with NH₄ OH, and extracted withmethylene chloride. The extract was washed with water and evaporated invacuo to dryness. The residue (11.7 g) was chromatographed on silica gelwith a eluting solvent system of methanol/ethyl acetate (10/90) to give17-cyclopropylmethylnorcodeine (10.68 g, 91% yield). IR (KBr)(ν, cm⁻¹):3300 (sharp, 6-OH); NMR (δ_(H))(CDCl₃): 6.65 (1, d, J, 8.2, 2-H), 6.523(1, d, J, 8.2, 1-H), 5.70 (1, dtd, J, 9.9, 1.8 & 1.2, 7-H), 5.29 (1, dt,J, 9.9 & 2.6, 8-H), 4.88 (1, dd, J, 6.6 & 1.2, 5-H), 4.20-4.13 (1, m,6-H), 3.84 (3, s, 3-OCH₃), 3.66 (1, dd, J, 6.3 & 3.3, 9-H), 2.94 (1, d,J, 18.6, 10-H.sub.β), 2.82 (1, dd, J, 12.1 & 3.9, 16-H_(a)), 2.70 (1,quintet, J, 2.8, 14-H), 2.44 (2, d, J, 6.3, --N--CH₂ -cyclopropyl), 2.44(1, overlap, 6-OH), 2.37 (1, td, J, 12.1 & 3.9, 16-H_(e)), 2.30 (1, dd,J, 18.5 & 6.4, 10-H.sub.α), 2.09 (1, td, J, 12.4 & 4.9, 15-H_(a)), 1.87(1, dd, J, 12.5 & 1.8, 15-H_(e)), 0.94-0.80 (1, m, --N--CH₂ --CH incyclopropyl ring), 0.54 (2, AB, CH--CH in cyclopropyl ring) and 0.15 (2,AB, CH--CH in cyclopropyl ring).

EXAMPLE 35

Preparation of 17-cyclopropylmethylnorcodeinone (5-5)

To a solution of DMSO (14.50 g, 185.6 mmol) in methylene chloride (80ml) at -78° C., was added a solution of oxalyl chloride (11.78 g, 92.8mmol) in methylene chloride (20 ml) in 20 min. After stirring at -78° C.for 20 min., a solution of 17-cyclopropylmethylnorcodeine (9.0 g, 26.5mmol) in methylene chloride (40 ml) was added dropwise in 50 min. Thereaction mixture was stirred at -74 to -76° C. for 3 hr, addedtriethylamine (9.39 g, 92.8 mmol), allowed to warm up to rt., addedmethylene chloride (200 ml), washed with water (10×50 ml), andevaporated in vacuo to dryness. The residue was mixed with hexane andfiltered to give 17-cyclopropylmethylnorcodeinone (8.85 g, 99% yield).IR (KBr)(ν, cm⁻¹): 1670 (st, sharp, --C═C--C═O); NMR (δ_(H))(CDCl₃):6.67 (1, d, J, 8.1, 2-H), 6.65 (1, dt, J, 10.2 & 1.07, 8-H), 6.57 (1, d,J, 8.1, 1-H), 6.07 (1, dt, J, 10.2 & 2.9, 7-H), 4.68 (1, s, 5-H), 3.85(3, s, 3-OCH₃), 3.69 (1, dd, J, 5.2 & 3.0, 9-H), 3.22 (1, dd, J, 5.2 &2.6,14-H), 3.00 (1, d, J, 18.3, 10-H.sub.β), 2.85 (1, dm, J, 11.8,16-H_(e)), 2.32 (1, dd, J, 18.3 & 5.0, 10-H.sub.α), 2.25 (1, td, J,11.9, 16-H_(a)), 2.07 (1, td, J, 11.9 & 4.6, 15-H_(a)), 1.84 (1, dt, J,12.0 & 2.0, 15-H_(e)), 2.45 (2, AB, N-CH₂ -cyclopropyl), 0.93-0.85 (1,m, N-CH₂ --CH in cyclopropyl ring), 0.55 (2, AB, CH--CH in cyclopropylring) and 0.15 (2, AB, CH--CH in cyclopropyl ring); MS (EI), m/e (%):337 (89.9, [M⁺ ]), 296 (17.4, [M-C₃ H₅ ]⁺) and 55 (100, [CH₂ C₃ H₅ ]⁺).

EXAMPLE 36

Preparation of 17-cyclopropylmethylnorcodeinone dienol acetate (5-6)

A mixture of 17-cyclopropylmethylnorcodeinone (3.55 g, 10.5 mmol),acetic anhydride (20 ml, 210.4 mmol), sodium acetate (1.3 g, 15.8 mmol),and toluene (6 ml) was heated at 71-73° C. for 14 hr. The reactionmixture was cooled, added methylene chloride (250 ml), water (50 ml),and sodium bicarbonate (73.5 g), stirred for 4 hr, and filtered. Theorganic portion of the filtrate was separated, washed with water (30ml), dried over anhydrous sodium sulfate, and evaporated in vacuo todryness. The residue (3.94 g) was chromatographed on silica gel with100% ethyl acetate to give 17-cyclopropylmethylnorcodeinone dienolacetate (2.87 g, 72% yield). IR (KBr)(ν, cm⁻¹): 1750 (st, sharp,--C═C--C═C--OAc); NMR (δ_(H))(CDCl₃): 6.67 (1, d, J, 8.1, 2-H), 6.58 (1,d, J, 8.1, 1-H), 5.79 (1, dd, J, 6.3 & 0.9, 7-H), 5.55 (1, d, J,6.3,8-H), 5.47 (1, s, 5-H), 3.92 (1., d, J, 7.0,9-H), 3.85 (3, s,3-OCH₃), 3.26 (1, d, J, 17.9, 10-H.sub.β), 2.89-2.82 (2, m, 16-H_(e) &16-H_(a)), 2.75 (1, dd, J, 18.6 & 7.0, 10-H.sub.α), 2.49 (2, d, J, 6.4,N--CH₂ -cyclopropyl), 2.32 (1, td, 12.0 & 4.5, 15-H_(a)), 2.20 (3, s,6-AcO), 1.71 (1, d, J, 12.2, 15-H_(e)), 0.93-0.86 (1, m, N--CH₂ --CH incyclopropyl ring), 0.55 (2, AB, CH--CH in cyclopropyl ring) and 0.15 (2,AB, CH--CH in cyclopropyl ring); MS (El), m/e (%): 380 (11.2, [M⁺ ]),379 (46.6, [M-H]⁺), 337 (14.4, [M-CH₃ CO]⁺), 282 (15.5, [M-CH₃ CO--CH₂C₃ H₅ ]⁺), 241 (33.2, [(M+H)--CH₃ CO--CH₂ C₃ H₅ --NCH₂ CH₂ ]), 55 (100,[CH₂ C₃ H₅ ]⁺) and 43 (29.5, [CH₃ CO]⁺).

EXAMPLE 37

Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone (5-7) from17-cyclopropylmethylnorcodeinone (5-5) by H₂ O₂ in HCOOH

A solution of 17-cyclopropylmethylnorcodeinone (0.20 g, 0.59 mmol),formic acid (90%, 0.304 g), water (0.504 g), EtOAc (0.27 g), andhydrogen peroxide (30%, 0.17 g) was heated at 42-43° C. for 15 hr, addedwater (20 ml), basified with Na₂ CO₃ (1.02 g), and extracted with EtOAc(80 ml & 2×20 ml). The combined extract was washed with water, driedover anhydrous sodium sulfate, and evaporated in vacuo to dryness togive 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.10 g, 56% yield).The R_(f) value in TLC and the IR spectrum of the product werecomparable to those obtained from an authentic sample.

EXAMPLE 38

Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone (5-7) from17-cyclopropylmethylnorcodeinone dienol acetate (5-6) by H₂ O₂ in HCOOH

A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (1.00 g,2.63 mmol), formic acid (8 ml, 90%), and hydrogen peroxide(0.37 g, 30%,3.26 mmol) was heated at 44-45° C. for 6 hr, added water (20 ml) andethyl acetate (80 ml), basified with sodium bicarbonate. The organicportion was separated, washed with water (15 ml), dried over anhydroussodium sulfate and evaporated in vacuo to dryness the residue (0.9 g)was chromatographed on silica gel with methanol/methylene chloride(2.5/97.5) to give 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.72 g,78% yield). IR (KBr)(ν, cm⁻¹): 1680 (st, sharp, C═C--C═O), 3480-3100(broad, 3335 (sharp), 14-OH); NMR (δ_(H))(CDCl₃): 6.70 (1, d, J, 8.2,2-H), 6.62 (1, dd, J, 10.1 & 0.5, 8-H), 6.59 (1, dd, J, 8.2 & 0.9, 1-H),6.18 (1, dd, J, 10.1 & 0.5, 7-H), 4.70(2, m, 5-H & 14--OH), 3.84 (3, s,3-OCH₃), 3.35 (1, d, J, 6.1, 9-H), 3.14 (1, d, J, 18.6, 10-H.sub.β),2.75 (1, ddd, J, 13.7, 4.3 & 1.4, 16-H_(e)), 2.55 (1, dd, J, 19.4 & 6.0,10-H.sub.α), 2.45 (2, d, J, 6.6, --N--CH₂ -cyclopropyl), 2.38 (1, td, J,13.8 & 4.3, 16-H_(a)), 2.26 (1, td, J, 12.1 & 3.7, 15-H_(a)), 1.70 (1,dd, J, 13.9 & 2.7, 15-H_(e)) 0.97-0.80 (1, m, N--CH₂ -CH in cyclopropylring), 0.58 (2, AB, CH--CH in cyclopropyl ring) and 0.17 (2, AB, CH--CHin cyclopropyl ring).

EXAMPLE 39

Preparation of 17-cyclopropylmethyl-14-hydroxynorcodeinone (5-7) from17-cyclopropylmethylnorcodeinone dienol acetate (5-6) by MCPBA

A solution of 17-cyclopropylmethylnorcodeinone dienol acetate (0.5 g,1.31 mmol), 3-chloroperbenzoic acid (0.36 g, 2.10 mmol) and oxalic acid(0.27 g,2.90 mmol) in acetic acid (7 ml) was stirred at rt. overnight,added cold water (35 ml), basified with sodium carbonate, and extractedwith methylene chloride (100 ml). The extract was washed with water(2×30 ml), dried over anhydrous sodium sulfate, and evaporated in vacuoto dryness. The residue (0.41 g) was chromatographed on silica gel togive 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.34 g, 74% yield).The R_(f) value in TLC and the IR spectrum of the product werecomparable to those obtained from an authentic sample.

EXAMPLE 40

Preparation of 3-methylnaltrexone (5-8)

A mixture of 17-cyclopropylmethyl-14-hydroxynorcodeinone (0.30 g, 0.85mmol) and Pd/C (5%, 0.45 g) in ethanol (35 ml) was hydrogenated in aParr hydrogenator at rt. under 28 psi of hydrogen gas. The mixture wasfiltered. The filtrate was evaporated in vacuo to dryness to give3-methylnaltrexone (0.30 g, 99% yield). IR (KBr)(ν, cm⁻¹): 1720 (st,sharp, C═O), 3380-3340 (broad, 14-OH); NMR (δ_(H))(CDCl₃): 6.70 (1, d,J, 8.2, 2-H), 6.60 (1, d, J, 8.1,1-H), 4.65 (1,s, 5-H), 3.91 (3, s,3-OCH₃), 3.17 (1, d, J, 6.0, 9-H), 3.06 (1, d, J, 18.2, 10-H.sub.β),3.03 (1, td, J, 14.4 & 5.2, 7-H_(a)), 2.70 (1, dd, J, 11.7 & 4.5,16-H_(e)), 2.58 (1, dd, J, 18.4 & 6.0, 10-H.sub.α), 2.41 (2, d, J, 6.6,--N--CH₂ -cyclopropyl), 2.41 (2, overlap, 14-OH & 16-H_(a)), 2.29 (1,dt, J, 14.5 & 3.1, 7-H_(e)), 2.12 (1, td, J, 11.9 & 3.5, 15-H_(a)), 1.88(1, ddd, J, 13.3, 5.2 & 3.1, 8-H_(e)), 1.67 (1, dd, J, 14.5 & 3.4,8-H_(a)), 1.58 (1, dt, J, 12.8 & 5.1, 15-H_(e)), 0.91-0.81 (1, m,--N--CH₂ --CH in cyclopropyl ring), 0.56 (2, AB, CH--CH in cyclopropylring) and 0.15 (2, AB, CH--CH in cyclopropyl ring).

EXAMPLE 41

Preparation of naltrexone from 3-methylnaltrexone (5-9)

A solution of 3-methylnaltrexone (0.48 g, 1.35 mmol) in methylenechloride (30 ml) was cooled with an ice-water bath, and then added asolution of boron tribromide (5.4 ml, 1 M solution in methylenechloride, 5.4 mmol). The reaction mixture was stirred at rt. for 15 hr,basified with NH₄ OH, and extracted with methylene chloride (60 ml). Theextract was washed with water (2×15 ml), dried over anhydrous sodiumsulfate, and evaporated in vacuo to dryness to give naltrexone (0.45 g,98% yield). IR (KBr)(ν, cm⁻¹): 1725 (st, sharp, C═O), 3620-3040 (broad,3-OH & 14-OH); NMR (δ_(H))(CDCl₃): 6.72 (1, d, J, 8.2, 2-H), 6.57 (1, d,J, 8.2, 1-H), 5.18 (2, s (broad), 3-OH & 14-OH), 4.69 (1,s, 5-H), 3.18(1, d, J, 5.8, 9-H), 3.05 (1, d, J, 18.5, 10-H.sub.β), 3.05 (1, td, J,14.3 & 5.3, 7-H_(a)), 2.71 (1, dd, J, 11.4 & 4.3, 16-H_(e)), 2.56 (1,dd, J, 18.8 & 5.9, 10-H.sub.α), 2.41 (2, d, J, 6.6, --N--CH₂-cyclopropyl), 2.41 (1, overlap, 16-H_(a)), 2.30 (1, dt, J, 14.7 & 3.1,7-H_(e)), 2.18 (1, td, J, 12.1 & 3.7, 15-H_(a)), 1.90 (1, dd, J, 13.3 &4.0, 8-H_(e)), 1.63 (1, dd, J, 14.4 & 3.2, 8-H_(a)), 1.57 (1, dm, J,9.9, 15-H_(e)), 0.91-0.81 (1, m, N--CH₂ --CH in .s: cyclopropyl ring),0.55 (2, AB, AB, CH--CH in cyclopropyl ring) and 0.15 (2, AB, CH--CH incyclopropyl ring).

F. Synthesis of Naltrexone From Morphine Through3-Benzyl-17-Cyclopropylmethylnormorphinone

6-1 (see 3-1 & 4-1)

6-2 (see 4-2)

EXAMPLE 42

Preparation of 3-benzyl-17-cyclopropylmethylnormorphine (6-4) from6-acetyl-3-benzylmorphine (6-2)

A solution of 6-acetyl-3-benzylmorphine (13.17 g, 31.5 mmol),1,8-bis-(dimethylamino)naphthalene (proton sponge, 1.34 g, 6.25 mmol),and 1-chloroethyl chloroformate (ACE-Cl, 7.03 g, 98% pure, 48.2 mmol) inClCH₂ CH₂ Cl was heated at reflux for 1.5 hrs. To this reaction mixture,was added MeOH (100 ml) and conc. HCl (8 drops). The reflux wascontinued for another 3 hr. The mixture was cooled and evaporated todryness in vacuo to give 3-benzylnormorphine hydrochloride as whiteflakes (15.05 g). IR (KBr)(ν, cm⁻¹): 3550 (m, sharp), 3400 (m, b), 3005(s, sharp); NMR (δ_(H))(DMSO-d₆): 10.35-9.62 (2 b, ⁺ NH₂ Cl⁻), 7.49-7.21(5, m, --C₆ H₅), 6.74 (1, d, J, 8.2, 2-H), 6.54 (1, d, J, 8.2, 1-H),5.77 (1, dm, J, 9.8, 7-H), 5.23 (1, dm, J, 10.2, 8-H), 5.13 (2, AB, OCH₂Ph), 4.89 (1, dd, J, 6.4 & 1.1, 5-H), 4.41 (d, J, 6.6, 9-H), 4.28-4.09(2, m, 6-H & OH), 3.4-2.8 (2, m, 10-H.sub.β & 10-H.sub.α), 3.4-2.8 (1,m, 14-H), 3.4-2.8 (2, m, 16-H_(a) & 16-H_(e)), 2.39 (1, td, J, 13.3 &5.1, 15-H_(a)), 2.02 (1, dm, J, 10.6, 15-H_(e)).

A suspension of 3-benzylnormorphine (31.5 mmol, crude),chloromethylcyclopropane (5.81 g, 64.2 mmol), and Na₂ CO₃ (20.54 g, 194mmol) in 2-propanol (150 ml) was heated at reflux for a day. The solventwas evaporated off in vacuo. The residue was added water and extractedwith CH₂ Cl₂ (250 ml). The extract was dried over anhydrous Na₂ SO₄ andevaporated in vacuo to dryness to give a crude product (16.08 g), whichwas chromatographed on silica gel (column: d=6 cm, I=13.5 cm; elutingsolvent: 4% MeOH in CH₂ Cl₂ ) to give3-benzyl-17-cyclopropylmethylnormorphine (13 g,100%). IR (KBr)(ν, cm⁻¹):3440 (m, b, --OH); NMR (δ_(H))(CDCl₃): 7.56-7.10 (5, m, --C₆ H₅), 6.69(1, d, J, 8.1, 2-H), 6.48 (1, d, J, 8.2,1-H), 5.64 (1, dm, J, 9.9, 7-H),5.28(1, dm, J, 9.8,8-H), 5.11 (2, AB, OCH₂ Ph), 4.85(1, dd, J, 6.5 &1.3, 5-H), 4.23-4.02 (1, m, 6-H), 3.64 (1, dd, J, 6.4 & 3.2, 9-H), 2.91(1, d, J, 18.4, 10-H.sub.β), 2.73 (1, dm, J, 11.8, 16-H_(e)), 2.72-2.55(1, m, 14-H), 2.72-2.55 (1, m, --OH), 2.48-2.20 (1, m, 16-H_(a)), 2.42(2, d, J, 6.4, N-CH₂ -cyclopropyl), 2.27 (1, dd, J, 18.6 & 6.2, 10-H),2.07 (1, td, J, 12.2 & 5.1, 15-H_(a)), 1.84 (1, dm, J, 13.0, 15-H_(e)),1.0-0.7 (1, m, m, N--CH₂ --CH in cyclopropyl ring), 0.53 (2, AB, CH--CHin cyclopropyl ring), 0.14 (2, AB, CH--CH in cyclopropyl ring).

EXAMPLE 43

Preparation of 3-benzyl-17-cyclopropylmethylnormorphinone (6-5)

To a solution of DMSO (5.88 g, 75.3 mmol) in CH₂ Cl₂ (80 ml) at -78° C.was added a solution of oxalyl chloride (4.51 g, 35.5 mmol) in CH₂ Cl₂(10 ml) in 10 min. This solution was allowed to stir at -78° C. for 20min. then was added a solution of 3-benzyl-17-cyclopropylmethylnorphine(7.06 g, 17.0 mmol) in CH₂ Cl₂ (30 ml) in 30 min. The resulting solutionwas allowed to stir at -78° C. for 3 hr. Et₃ N (20 ml, 148 mmol) wasadded. The mixture was allowed to warm up to rt., washed with water(5×80 ml), dried over anhydrous Na₂ SO₄, and evaporated in vacuo todryness to give a reddish oil (7.98 g), which was chromatographed onsilica gel (column: d=5 cm, I=19 cm; eluting solvent: 5% MeOH in EtOAc)to give 3-benzyl-17-cyclopropylmethylnormorphinone (5.56 g, 79% yield).IR (KBr)(ν, cm⁻¹): 1670 (s, sharp, C═C--C═O); NMR (δ_(H))(CDCl₃):7.52-7.18 (5, m, --C₆ H₅), 6.69 (1, d, J, 8.2, 2-H), 6.64 (1, dd, J,10.5 & 2.2, 8-H), 6.52 (1, d, J, 8.2,1-H), 6.07 (1, dd, J, 10.2 & 3.1,7-H), 5.17 (2, s, OCH₂ Ph), 4.70 (1, s, 5-H), 3.68 (1, dd, J, 5.4 & 2.9,9-H), 3.29-3.16 (1, m, 14-H), 2.98 (1, d, J, 18.3, 10-H.sub.β), 2.83 (1,dm, J, 10.7,16-H_(e)), 2.6-2.3 (1, m, 10-H.sub.α), 2.41 (2, AB, N--CH₂-cyclopropyl), 2.24 (1, td, J, 11.7 & 3.2,16-H_(a)), 2.07 (1, td, J,11.6 & 4.8, 15-H_(a)), 1.84 (1, dm, J, 13.0, 15-H_(e)), 1.0-0.78 (1, m,N--CH₂ --CH in cyclopropyl ring), 0.55 (2, AB, CH--CH in cyclopropylring), 0.15 (2, AB, CH--CH in cyclopropyl ring); MS (EI), m/e (%): 413(M⁺, 8), 322 (28, [M--CH₂ Ph]⁺), 91 (68, [CH₂ Ph]⁺), 55 (100, [CH₂ C₃ H₅]⁺).

EXAMPLE 44

Preparation of 3-benzyl-17-cyclopropylmethylnormorphinone dienol acetate(6-6)

A mixture of 3-benzyl-17-cyclopropylmethylnormorphinone (4.34 g, 10.5mmol), NaOAc (1.92 g, 23.4 mmol), Ac₂ O (44.14 g, 432.4 mmol) in toluene(10 ml) was heated at 100° C. for 20 hr., cooled, basified with aqueousNaHCO₃, and extracted with CH₂ Cl₂ (300 ml). The extract was washed withwater (3×150 ml), dried over anhydrous Na₂ SO₄, and evaporated in vacuoto dryness to give an oil (5.57 g), which was chromatographed on silicagel (column: d=5 cm, I=19.5 cm; eluting solvent: EtOAc) to obtain3-benzyl-17-cyclopropylmethylnormorphinone dienol acetate (3.0 g, 63%yield). IR (KBr)(ν, cm⁻¹): 1760 (s, sharp, C═C--C═C--OAc); NMR(δ_(H))(CDCl₃): 7.51-7.20 (5, m, C₆ H₅), 6.68 (1, d, J, 8.1, 2-H), 6.52(1, d, J, 8.3, 1-H), 5.77 (1, dd, J, 6.3 & 0,9, 7-H), 5.55 (1, d, J,6.3, 8-H), 5.48 (1, s, 5-H), 5.14 (2, s, OCH₂ Ph), 3.92 (1, d, J, 7.0,9-H), 3.25 (1, d, J, 17.9, 10-H.sub.β), 2.95-2.80 (2, m, 16-H_(a) &16-H_(e)), 2.74 (1, dd, J, 18.5 & 7.3, 10-H.sub.α), 2.49 (2, s, N-CH₂-cyclopropyl), 2.29 (1, td, J, 12.4 & 6.5, 15-H_(a)), 2.19 (3, s, m,C═C--C═C--OAc), 1.72 (1, dm, J, 12.4, 15-H_(e)), 1.0-0.8 (1, m, CH₂ --CHin cyclopropyl ring), 0.55 (2, AB, CH--CH in cyclopropyl ring), 0.15 (2,AB, CH--CH in cyclopropyl ring); MS (EI), m/e (%): 455 (M⁺, 16), 364(27, [M--CH₂ Ph]⁺), 322 (28, [M--CH₂ Ph--CH₂ ═C═O]⁺), 91 (68, [CH₂Ph]⁺), 55 (100, [CH₂ C₃ H₅ ]⁺).

EXAMPLE 45

Preparation of 3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone(6-7) from 3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone dienolacetate (6-6) by MCPBA

A solution of 3-benzyl-17-cyclopropylmethylnormorphinone dienol acetate(0.61 g, 1.34 mmol), oxalic acid (0.25 g, 2.8 mmol), and3-chloroperbenzoic acid (0.36 g, 57-86%, 1.2-1.8 mmol) in AcOH (5.44 g,88.9 mmol) was stirred at rt. for 5 hr, basified with cold aqueousNaHCO₃, extracted with CH₂ Cl₂ (120 ml). The extract was dried overanhydrous Na₂ SO₄ and evaporated in vacuo to dryness to give an oilyresidue (0.93 g), which was chromatographed on silica gel (column:d=2.54 cm, I=23 cm; eluting solvent: 1% MeOH in CH₂ Cl₂) to obtain3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone (0.46 g, 80%yield). The R_(f) value in TLC and the IR spectrum of the product werecomparable to those obtained from an authentic sample.

EXAMPLE 46

Preparation of 3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone(6-7) from 3-benzyl-17-cyclopropylmethyl-14-hydroxymorphinone dienolacetate (6-6) by H₂ O₂ in HCOOH

A solution of 3-benzyl-17-cyclopropylmethylnormorphinone dienol acetate(0.91 g, 2.0 mmol), formic acid (6.02 g, 90%, 117.7 mmol), and H₂ O₂(0.28 g, 30%, 2.47 mmol) was heated at 35-46° C. for 3 hr., basifiedwith cold aqueous NaHCO₃, extracted with CH₂ Cl₂ (200 ml). The extractwas washed with water (50 ml), dried over anhydrous Na₂ SO₄ andevaporated in vacuo to dryness to give an oily residue (1.15 g), whichwas chromatographed on silica gel (column: d=2.54 cm, I=19 cm; elutingsolvent: 3% MeOH in CH₂ Cl₂) to obtain3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone (0.75 g, 87%yield). IR (KBr)(ν, cm⁻¹): 3300 (m, OH), 1680 (s, sharp, C═C--C═O); NMR(δ_(H))(CDCl₃): 7.43-7.19 (5, m. C₆ H₅), 6.71 (1, d, J, 8.1, 2-H), 6.62(1, d, J, 9.8, 8-H), 6.53 (1, d, J, 8.2, 1-H), 6.18 (1, d, J, 10.1,7-H), 5.16 (2, s, OCH₂ Ph), 4.73 (1, s, 5-H), 3.34 (1, d, J, 6.1, 9-H),3.12 (1, d, J, 18.6, 10-H.sub.β), 2.74 (1, dm, J, 11.1, 16-H_(e)), 2.53(1, dd, J, 19.2 & 6.0, 10-H.sub.α), 2.55-2.35 (1, b, --OH), 2.55-2.35(1, m, 15-H_(a)), 2.44 (2, d, J, 6.4, N-CH₂ -cyclopropyl), 2.25 (1, td,J, 11.8 & 3.4,16-H_(a)), 1.69 (1, dm, J, 13.0, 15-H_(e)), 0.98-0.78 (1,m, CH₂ --CH in cyclopropyl ring), 0.58 (2, AB, CH--CH in cyclopropylring), 0.16 (2, AB, CH--CH in cyclopropyl ring); MS (EI), m/e (%): 429(M⁺, 2) 338 (75, [M--CH₂ Ph]⁺), 91 (100, [CH₂ Ph]⁺), 55 (97, [CH₂ C₃ H₅]⁺).

EXAMPLE 47

Preparation of naltrexone (6-8) from3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone (6-7)

A mixture of 3-benzyl-17-cyclopropylmethyl-14-hydroxynormorphinone (0.40g, 0.93 mmol) and 5% Pd/C (0.25 g) in 2-propanol (60 ml) washydrogenated under 30 psi at rt. overnight, filtered through celite, andevaporated to dryness to give naltrexone (0.32 g, 100% yield). The R_(f)value in TLC and the IR spectrum of the product were comparable to thoseobtained from an authentic sample.

Although the invention has been illustrated by the preceding examples,they are not to be construed as being limited to the materials employedtherein, but rather the invention is directed to the generic ashereinbefore disclosed. Various modifications and embodiments can bemade without departing from the spirit or scope thereof.

What is claimed is:
 1. A process of preparing noroxymorphone of theformula: ##STR25## from morphine comprising the steps of: (1) protectingthe hydroxy groups in the 3- and 6-positions of morphine so as to form3(O), 6(O)-diprotected-morphine of formula (A-a) wherein the 3-positionprotecting group P is benzyl or substituted-benzyl and the 6-positionprotecting group is an acyl group, R"C(O), wherein R" is lower alkyl of1-4 carbon atoms; ##STR26## (2) de-methylating the N-methyl on the 17position of the 3(O), 6(O)-diprotected-morphine and hydrolizing the6-acyl group so as to form 3(O)-protected-normorphine of formula (A-b);##STR27## (3) reacting the 3(O)-protected-normorphine so as to form17-benzyl or substituted-benzyl-3(O)-protected-normorphine of formula(A-c); ##STR28## wherein P is as defined above and wherein Q and Q' areindividually selected from the group consisting of hydrogen, loweralkyl, trifluoromethyl, nitro, dialkylamino and cyano;(4) oxidizing the17-benzyl or substituted-benzyl-3(O)-protected-normorphine of formula(A-c) so as to form 17-benzyl orsubstituted-benzyl-3(O)-protected-normorphinone of formula (A-d);##STR29## (5) and either by (5a) or (5b): (5a) converting 17-benzyl orsubstituted-benzyl-3(O)-protected-normorphinone of formula (A-d) to the14-hydroxy-17-benzyl or substituted-benzyl-3(O)-protectednormorphinone(A-e); ##STR30## or (5b) first converting 17-benzyl orsubstituted-benzyl-3(O)-protected-normorphinone (A-d) to thecorresponding 17-benzyl orsubstituted-benzyl-3(O)-protected-normorphinone dienol acylate offormula (A-f); ##STR31## converting 17-benzyl orsubstituted-benzyl-3(O)-protected-normorphinone dienol acylate (A-f) toform 14-hydroxy-17-benzyl orsubstituted-benzyl-3(O)-protected-normorphinone of formula (A-e);##STR32## (6) hydrogenating 17-benzyl orsubstituted-benzyl-14-hydroxy-3(O)-protected-normorphinone (A-e) to formnoroxymorphone.